The estrogen receptor (ER) is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. Estrogens play an important role in the regulation of a number of physiological processes, both in females and males. In humans, two different ER subtypes are known: ERα and ERβ, each with a distinct tissue distribution and with different biological roles. ERα has high presence in endometrium, breast cancer cells, ovarian stroma cells, and in the hypothalamus. The expression of the ERβ protein has been documented in kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, bladder, ovary, testis, and endothelial cells. For a review see: J. W. Ullrich and C. P. Miller, Expert Opin. Ther. Patents, 16 (2006) 559-572.
Well-known examples of SERMs are tamoxifen and raloxifene. Tamoxifen, for example, behaves like an estrogen in bone and endometrium, whereas it behaves like an anti-estrogen in breast tissue. SERMs are furthermore characterized by two common structural features: a phenolic hydroxyl group (or a bioisostere thereof) and a side chain containing a basic amine. At the time of administration in vivo, the hydroxyl group of a SERM may not yet be present; it may be formed in vivo by de-masking of a prodrug (for example by demethylation of a phenolic methoxy group or by hydrolysis of a phenolic ester group) or by metabolic introduction (for example the metabolic conversion of tamoxifen into 4-hydroxy-tamoxifen, an active metabolite of tamoxifen). Examples of side chains containing a basic amine are 2-(dimethylamino)ethoxy (like in tamoxifen), 2-(1-piperidinyl)ethoxy (like in raloxifene), and 2-(1-pyrrolidinyl)ethoxy (like in lasofoxifene). Upon binding of a SERM to the estrogen receptor, the basic amine in the side chain forms an interaction with amino acid residue Asp351 (in ERα) or Asp303 (in ERβ) resulting in a conformational change of the receptor. For reviews on SERMs see: C. P. Miller, Current Pharmaceutical Design 8 (2002) 2089-2111; V. C Jordan, J. Med. Chem. 46 (2003) 883-908, and J. H. Pickar et al.; Maturitas 67 (2010) 129-138.
Breast cancer is the predominant neoplastic disease in women. ERα is a major driver of breast cancer progression. Multiple existing treatment approaches aim to reduce estrogen levels or block its binding to ERα thereby minimizing tumor progression or even inducing tumor regression in ER-positive breast cancer. Tamoxifen is a first generation SERM used for first-line treatment of ER-positive breast cancer (see V. C. Jordan, Nature Reviews Drug Discovery, 2 (2003) 205-213). Efficacy in breast cancer treatment is seriously compromised by intrinsic or newly developed resistance to anti-hormonal therapy such as treatment with tamoxifen or aromatase inhibitors. Such resistance can exist or develop as a result of ER phoshorylation or regulation of key components in hormone receptor and/or growth factor signal transduction pathways (see V. C. Jordan and B. W. O'Malley, J. Clin. Oncol. 25 (2007) 5815-5824; V. C. Jordan, J. Nat. Cancer Inst., 98 (2006) 657-659; S. J. Cleator et al., Clinical Breast Cancer 9 (2009) S6-S17).
Tamoxifen resistance is driven by the residual agonist activity of tamoxifen and its 4-OH metabolites. Second generation SERMs such as toremifene, droloxifene, idoxifene, arzoxifene, and raloxifene have failed to improve upon the efficacy of tamoxifen in the treatment of ER-positive breast cancer and/or demonstrated cross-resistance with each other (V. Deshmane et al., J. Clin. Oncol. 25 (2007) 4967-4973); J. H. Pickar et al., Maturitas 67 (2010) 129-138).
Fulvestrant, a steroidal C7-substituted 17β-estradiol derivative and a pure ER antagonist without the partial agonist activity which is so typical for the SERMs, is the only marketed SERD (Selective Estrogen Receptor Downregulator) efficacious in second-line treatment of breast cancer. Besides antagonizing ERs, fulvestrant also effectively downregulates ERα protein levels in cells. This SERD activity inhibits ERα-driven proliferation and tumor growth (in contrast to tamoxifen which upregulates ERα). Fulvestrant, when administered i.m. once a month at 250 mg is equally effective to tamoxifen in treatment of ER-positive advanced breast cancer (A. Howell et al., J. Clin. Oncol. 22 (2004) 1605-1613). In second-line treatment of ER-positive tamoxifen-resistant breast cancer, fulvestrant, when administered i.m. once a month at 250 mg, is equally effective to aromatase inhibitors, despite relatively poor bioavailability and/or target exposure which limits its clinical efficacy (Robertson et al., San Antonio Breast Cancer Symposium, 2009; Linden et al., San Antonio breast Cancer Symposium, 2007).
Other known SERDs are ICI 164,384, i.e. a structural analogue of fulvestrant, GW5638, i.e. a structural analogue of tamoxifen, and GW7604, i.e. a structural analogue of 4-hydroxy-tamoxifen. For a review on SERDs see: M. Fan et al., Breast Cancer Res. Treat. 103 (2007) 37-44.
Merck has reported a series of 2,3-dihydrobenzo[b][1,4]-oxathiine derivatives, in which a modified (i.e. a bis-methylated pyrrolidinylethoxy) basic amine side chain all at once behaved as a SERD instead of as a SERM. However, when said modified basic amine side chain was placed on other SERM-derived chemical scaffolds, such as the benzothiophene of raloxifene, the tetrahydronaphthalene of lasofoxifene and the indole of bazedoxifene, these modified compounds did not behave as SERDs. See page 561 of J. W. Ullrich and C. P. Miller, Expert Opin. Ther. Patents, 16 (2006) 559-572, and references 18 and 101-103 cited therein.
Hence, there is a need for new, potent ERα antagonists, which would preferably have ER downregulating activity (in breast cancer cells), do not stimulate proliferation in ER-positive, hormone treatment-resistant breast cancer cells, be orally administrable, and be useful in the treatment of inter alia ER-positive, hormone treatment-resistant breast cancer.
Apart from the treatment of breast cancer, SERMs have also been used in the treatment of a number of other disorders and/or diseases. The treatment of ovulatory dysfunction by tamoxifen and clomiphene citrate, which induce ovulation, is described by A. Steiner et al. in Human Reproduction 20 (2005) 1511-1515; and by J. H. Pickar et al. in Maturitas 67 (2010) 129-138. J. H. Pickar et al. in Maturitas 67 (2010) 129-138 also describe the treatment of uterine cancer, endometrium cancer, osteoporosis, prostate cancer, and benign prostatic hypertrophy using SERMs. S. J. Ellem and G. P. Risbridger in Nature Reviews Cancer 7 (2007) 621-627 also describe the treatment of prostate cancer and benign prostatic hyperplasia (or hypertrophy). The treatment of ovarian cancer is described by G. M. Clinton and W. Hua in Crit. Rev. Oncol. Hematol. 25 (1997) 1-9. S. E. Bulun in N. Engl. J. Med. 360 (2009) 268-279 reviews the role of estrogen and estrogen receptor signaling in endometriosis.